Tunneling Nanotubes Mediate Adaptation of Glioblastoma Cells to Temozolomide and Ionizing Radiation Treatment

Silvana Valdebenito, Alessandra Audia, Krishna P.L. Bhat, George Okafo, Eliseo A. Eugenin

    Research output: Contribution to journalArticlepeer-review

    38 Scopus citations

    Abstract

    Glioblastoma (GBM) is the most prevalent and aggressive tumor in the central nervous system. Surgical resection followed by concurrent radiotherapy (ionizing radiation [IR]) and temozolomide (TMZ) is the standard of care for GBM. However, a large subset of patients offer resistance or become adapted to TMZ due mainly to the DNA repair enzyme O6-methylguanine-DNA methyltransferase (MGMT). Thus, alternative mechanisms of MGMT deregulation have been proposed but are heretofore unproven. We show that heterogeneous GBM cells express tunneling nanotubes (TNTs) upon oxidative stress and TMZ/IR treatment. We identified that MGMT protein diffused from resistant to sensitive cells upon exposure to TMZ/IR, resulting in protection against cytotoxic therapy in a TNT-dependent manner. In vivo analysis of resected GBM tumors support our hypothesis that the MGMT protein, but not its mRNA, was associated with TNT biomarkers. We propose that targeting TNT formation could be an innovative strategy to overcome treatment resistance in GBM.

    Original languageEnglish (US)
    Article number101450
    JournaliScience
    Volume23
    Issue number9
    DOIs
    StatePublished - Sep 25 2020

    Keywords

    • Cancer
    • Cell Biology

    ASJC Scopus subject areas

    • General

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